Scheme Of Characterization

Systematic development cycles are more likely to be efficient and should result in a definite specification for the lead compound; Scheme 1 shows a typical flow chart for the characterization that leads to the development of specifications for the lead compound.

Examples of properties that are routinely examined include solubility, water content, particle size, crystal properties, biological structure, chirality, and so on. The compatibility of the drug substance with excipients should be discussed. For products that contain more than one drug substance, the compatibility of the drug substances with each other should also be evaluated. Whereas the dosage form considerations are still to evolve, based on a prospective dosage form, the specifications should include those parameters that may be relevant. For example, if the final dosage form intended is an injectable product, solubility and thermal stability (to autoclaving) are important considerations. Table 1 lists some common study protocols for different dosage forms.

The experience and data accumulated during the preformulation stage proves pivotal to the development of the dosage form based on the specifications developed. A specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which a new drug substance or new drug product should conform to be considered acceptable for its intended use. Conformance to specifications means that the drug substance and/or drug product, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards

Scheme 1 Steps that lead to the development of specifications for new lead compounds.

Scheme 1 Steps that lead to the development of specifications for new lead compounds.

Table 1 Study Factors for Various Prospective Dosage Forms

Prospective dosage form

Study factors


Oral solids

Oral liquids Semisolids

Solubility, micellization, thermal stability, chemical stability, packaging component interaction (glass, stoppers), photostability, physical stress (particularly for protein drugs), buffer interactions, and viscosity.

Solubility, dissolution, polymorphism, chirality, particle size, powder flow, chemical stability, photostability, compressibility, hygroscopicity, and excipient interactions.

Solubility, polymorphic conversions, chirality, excipient interactions, chemical stability, photostability, pH effects, and container interactions (e.g., type III glass).

Solubility, dissolution, particle size, polymorphism, chirality, chemical stability, photostability, viscosity, and excipient interactions.

that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval. It is possible that, in addition to release tests, a specification may list in-process tests, periodic or skip tests, and other tests that are not always conducted on a batch-by-batch basis. When a specification is first proposed, justification should be presented for each procedure and each acceptance criterion included. The justification should refer to relevant development data, pharmacopoeia standards, test data for drug substances and drug products used in toxicology and clinical studies, and results from accelerated and long-term stability studies, as appropriate. Additionally, a reasonable range of expected analytical and manufacturing variability should be considered. Test results from stability and scale-up/validation batches, with emphasis on the primary stability batches, should be considered in setting and justifying specifications.

The U.S. FDA recommends the initiative, process analytical technology (PAT), which applies to both drug substances and drug products (1). PAT is a system for designing, analyzing, and controlling the manufacture through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality. The goal of PAT is to understand and control the manufacturing process, which is consistent with our current drug quality system: quality cannot be tested into products; it should be built-in or should be by design. It is important to note that the term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner. There are many current and new tools available that enable scientific, risk-managed pharmaceutical development, manufacture, and quality assurance. These tools, when used within a system can provide effective and efficient means for acquiring information to facilitate process understanding, develop risk-mitigation strategies, achieve continuous improvement, and share information and knowledge. In the PAT framework, these tools can be categorized as:

• Multivariate data acquisition and analysis tools

• modern process analyzers or process analytical chemistry tools

• process and endpoint monitoring and control tools

• continuous improvement and knowledge management tools

An appropriate combination of some, or all, of these tools may be applicable to a single-unit operation, or to an entire manufacturing process and its quality assurance. A variety of sophisticated softwares, such as RAPID-Pharma (2) are now available to consolidate many functions required to manage the initiatives related to PAT.

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